The present invention relates to novel fatty acid derivatives of the camptothecin class of compounds, their methods of preparation and use as antitumor agents.
Cancer cells do not contain molecular targets that are completely foreign to the host. Therefore, most anticancer chemotherapies have relied primarily on the enhanced proliferative rate of cancer cells. Anticancer drugs kill the rapidly dividing tumor cells in either S or G2-M phases of the cell cycle while sparing the quiescent tumor and normal cells in G1 or G0 phases (Tannock, I. F. in DeVita et al., eds. Cancer: Principle and Practice of Oncology: 3-13, J. B. Lippincott, Philadelphia, 1989). The fraction of tumor cells that are dividing at any time varies depending upon tumor type and the growth stage of the tumor. In general, faster-cycling tumors e.g., lymphomas, testicular tumors, and some childhood tumors, are more susceptible to chemotherapy than are the more common types of solid tumors with slowly cycling or noncycling cells. However, some normal cells such as bone marrow and intestinal mucosa also cycle rapidly, making them susceptible to the toxic side effects of chemotherapeutic drugs. Thus, finding a unique property of tumor biochemistry or physiology that can be exploited to target chemotherapeutic drugs to tumors to maintain an effective concentration for longer times and thereby create a greater therapeutic advantage is important to a successful cancer therapy. There remains a need in the art for effective cancer therapeutics.
The present invention provides compounds that can be used for the treatment of mammalian cell proliferating disease, e.g., cancer. The present invention provides conjugates of DHA and camptothecin (CPT) compounds that have a greatly improved therapeutic efficacy, compared to free camptothecin compounds. These DHA-CPT conjugates have been tested in experimental animal tumor models, and shown excellent antitumor activity compared to the free camptothecin compounds. The DHA-CPT compounds provided by this invention can be used to treat cancer. The compounds are of the following formula (I) or pharmaceutically acceptable salts thereof:
Long chain unsaturated fatty acidxe2x80x94linkerxe2x80x94CPTxe2x80x83xe2x80x83(Formula I)
wherein:
the Long-chain unsaturated fatty acid is C12-C22 mono or poly unsaturated fatty acids, which include, but are not limited to, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA);
the linker is -(alkyl)m-(aryl)n-C(O)xe2x80x94 or -(aryl)m-(alkyl)n-C(O)xe2x80x94; wherein: m and n are independently 0-3, and m+nxe2x89xa71; and
CPT is a camptothecin compound with the following general structure (Formula II): 
xe2x80x83wherein: R1-R5 are H, halo, OH, NO2, NH2, alkyl, O-alkyl, NH-alkyl, N(alkyl)2, ester, or amide, and can be the same or different. When any of R1-R5 is amino, the compounds are the free bases and their acid addition salts, such as HCl and H2SO4.
In preferred embodiments of the compounds of formula (I), the fatty acids are DHA and EPA, the linker is selected from formula (III) and CPT is camptothecin, 9-aminocamptothecin, 10-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin and 9-N,N-dimethylaminomethyl-10-hydroxycamptothecin, or their acid addition salts, such as HCl and H2SO4. 
A preferred composition of the present invention is: 
Another preferred composition of the present invention is: 
Yet another preferred composition of the present invention is: 
The present invention also provides a method for the treatment of mammalian cell proliferating disease, e.g., cancer. The method comprises administering to a patient an effective amount of one of the compounds of the following formula, or pharmaceutically acceptable salts thereof:
Long chain unsaturated fatty acidxe2x80x94linkerxe2x80x94CPTxe2x80x83xe2x80x83(Formula I)
wherein:
the Long-chain unsaturated fatty acid is C12-C22 mono or poly unsaturated fatty acids, which include, but are not limited to, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA);
the linker is -(alkyl)m-(aryl)n-C(O)xe2x80x94 or -(aryl)m-(alkyl)n-C(O)xe2x80x94; wherein: m and n are independently 0-3, and m+nxe2x89xa71; and
CPT is a camptothecin compound with the following general structure (Formula II): 
xe2x80x83wherein: R1-R5 are H, halo, OH, NO2, NH2, alkyl, O-alkyl, NH-alkyl, N(alkyl)2, ester, or amide, and can be the same or different. When any of R1-R5 is amino, the compounds are the free bases and their acid addition salts, such as HCl and H2SO4.
In preferred embodiments of the compounds of formula (I), the fatty acids are DHA and EPA, the linker is selected from formula (III) and CPT is camptothecin, 9-aminocamptothecin, 10-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin and 9-N,N-dimethylaminomethyl-10-hydroxycamptothecin, and their acid addition salts, such as HCl and H2SO4. 
In a preferred embodiment of the present invention, the method comprises administering to a patient an effective amount of one of the compounds of the following formula, or pharmaceutically acceptable salts thereof: 
The compounds of the present invention can also be used as an adjuvant to conventional cancer therapy to treat apoptosis-resistant tumors and in the treatment of other diseases to overcome drug resistance. The compounds of the present invention can be administered simultaneously or sequentially with at least one conventional cancer therapy. The conventional cancer therapy can be radiation therapy, chemotherapy, and/or biologic therapy. Preferred chemotherapy includes an antimetabolite, an alkylating agent, a plant alkaloid, and an antibiotic. Preferred antimetabolite includes methotrexate, 5-fluorouracil, 6-mercaptopurine, cytosine arabinoside, hydroxyurea, and 20-chlorodeoxyadenosine. Preferred alkylating agent includes cyclophosphamide, melphalan, busulfan, cisplatin, carboplatin, chlorambucil, and nitrogen mustards. Preferred plant alkaloid includes vincristine, vinblastine, and VP-16. Preferred antibiotic includes doxorubicin, daunorubicin, mitomycin c, and bleomycin. Alternate preferred chemotherapy includes decarbazine, mAMSA, hexamethylmelamine, mitoxantrone, taxol, etoposide, dexamethasone. Preferred radiation therapy includes photodynamic therapy, radionucleotides, and radioimmunotherapy. Preferred biologic therapy includes immunotherapy, differentiating agents, and agents targeting cancer cell biology.
The above description sets forth rather broadly the more important features of the present invention in order that the detailed description thereof that follows may be understood, and in order that the present contributions to the art may be better appreciated. Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the accompanying drawings. It is to be understood, however, that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention, for which reference should be made to the appended claims.
These and other objects of the present invention will be apparent from the detailed description of the invention provided below.